Hexahydro-1h-4,7-methanoisoindole-1,3-dione compounds

ABSTRACT

The present invention is directed to therapeutic agents which are atypical antipsychotics and which are useful in the treatment of neurological and psychiatric disorders associated with dopamine D2 and serotonin 5-HT2A neurotransmission dysfunction.

BACKGROUND OF THE INVENTION

Schizophrenia is a debilitating psychiatric disorder characterized by acombination of negative (blunted affect, withdrawal, anhedonia) andpositive (paranoia, hallucinations, delusions) symptoms as well asmarked cognitive deficits. While the etiology of schizophrenia iscurrently unknown, the disease appears to be produced by a complexinteraction of biological, environmental, and genetic factors. Atypicalantipsychotics form the front line in the treatment of schizophrenia andmore recently in bipolar disorder. However, up to 30% of schizophrenicpatients are not adequately treated by currently available medication.While there are a number of atypical antipsychotic agents currentlyavailable, these agents suffer from a high rate of discontinuation dueto either patient and/or physician dissatisfaction with efficacy orsafety/tolerability. Atypical antipsychotics possess a pharmacologywhich is thought to underlie their ability to achieve efficacy atpositive symptoms via antagonism at dopamine D2 and serotonin 5-HT_(2A)receptors. These activities produce some efficacy on negative symptomsbut also contribute to adverse side effects. These adverse side effectsinclude weight gain /metabolic effects (thought to be associated withantagonism at 5-HT_(2C) and antagonism at histamine H1 receptors),extra-pyramidal effects and prolactin secretion (thought to beassociated with antagonism at dopamine D2 receptors), sedation (thoughtto be associated with antagonism at α1 adrenergic and antagonism athistamine H1 receptors) and cognitive impairment (thought to beassociated with antagonism at muscarinic M1 receptors). Accordingly,there is a need in the art for atypical antipsychotic agents with betterefficacy on positive symptoms, negative symptoms and/or decreasedadverse side effects.

SUMMARY OF THE INVENTION

The present invention is directed to therapeutic agents which areatypical antipsychotics and which are useful in the treatment ofneurological and psychiatric disorders associated with dopamine D2 andserotonin 5-HT2A neurotransmission dysfunction.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   R¹ is C₁₋₆alkyl, which is unsubstituted or substituted with 1-6    fluoro, wherein R¹ and the hydroxyl group on the ring are attached    to the same carbon atom;-   or a pharmaceutically acceptable salt thereof.

Within this embodiment, the present invention includes compounds whereinR¹ is C₁₋₃alkyl which is unsubstituted or substituted with 1-6 fluoro.

Further within this embodiment, the present invention includes compoundswherein R¹ is selected from the group consisting of:

-   -   (1) methyl,    -   (2) ethyl,    -   (3) n-propyl,    -   (4) isopropyl,    -   (5) trifluoromethyl, and    -   (6) trifluoroethyl.

Further within this embodiment, the present invention includes compoundswherein R¹ is methyl. Also further within this embodiment, the presentinvention includes compounds wherein R¹ is ethyl. Also further withinthis embodiment, the present invention includes compounds wherein R¹ istrifluoromethyl.

An embodiment of the present invention includes compounds of the formulaIa:

wherein R¹ is defined herein;

-   or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa′:

wherein R¹ is defined herein;

-   or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein R¹ is defined herein;

-   or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb′:

wherein R¹ is defined herein;

-   or a pharmaceutically acceptable salt thereof.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the subject compounds of theExamples herein and pharmaceutically acceptable salts thereof andindividual enantiomers and diastereomers thereof.

The compounds of the present invention may contain one or more chiralcenters and can thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers and it is intended thatall of the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within the ambit ofthis invention. The present invention is meant to comprehend all suchisomeric forms of these compounds.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halo or halogen as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₆alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includethe ammonium, calcium, magnesium, potassium, and sodium salts. Salts inthe solid form may exist in more than one crystal structure, and mayalso be in the form of hydrates. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like. When the compound of thepresent invention is basic, salts may be prepared from pharmaceuticallyacceptable non-toxic acids, including inorganic and organic acids. Suchacids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid, and the like. Particular embodiments citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of the present invention are meant to also include thepharmaceutically acceptable salts. Exemplifying the invention is the useof the compounds disclosed in the Examples and herein.

The subject compounds are useful in a method of treating a neurologicalor psychiatric disorder associated with dopamine D2 and serotonin 5-HT2Aneurotransmission dysfunction in a patient such as a mammal in need ofsuch inhibition comprising the administration of an effective amount ofthe compound. In addition to primates, especially humans, a variety ofother mammals can be treated according to the method of the presentinvention.

The present invention is further directed to a method for themanufacture of a medicament for treating neurological or psychiatricdisorder associated with dopamine D2 and serotonin 5-HT2Aneurotransmission dysfunction in humans and animals comprising combininga compound of the present invention with a pharmaceutical carrier ordiluent.

The subject treated in the present methods is generally a mammal, inparticular, a human being, male or female, in whom therapy is desired.The term “therapeutically effective amount” means the amount of thesubject compound that will elicit the biological or medical response ofa tissue, system, animal or human that is being sought by theresearcher, veterinarian, medical doctor or other clinician. It isrecognized that one skilled in the art may affect the neurological andpsychiatric disorders by treating a patient presently afflicted with thedisorders or by prophylactically treating a patient afflicted with suchdisorders with an effective amount of the compound of the presentinvention. As used herein, the terms “treatment” and “treating” refer toall processes wherein there may be a slowing, interrupting, arresting,controlling, or stopping of the progression of the neurological andpsychiatric disorders described herein, but does not necessarilyindicate a total elimination of all disorder symptoms, as well as theprophylactic therapy to retard the progression or reduce the risk of thenoted conditions, particularly in a patient who is predisposed to suchdisease or disorder.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof. The terms“administration of and or “administering a” compound should beunderstood to mean providing a compound of the invention or a prodrug ofa compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asatypical antipsychotics may be demonstrated by methodology well known inthe art. In particular, the compounds of the following examples hadactivity in reference assays by exhibiting high affinity antagonism fordopamine D2, serotonin 5-HT2A, α2C adrenergic receptors, partial agonismat 5-HT1A receptors and weak affinity at 5-HT2C, histamine H1 and M1receptors.

With respect to other imide compounds such as those disclosed in U.S.Pat. No. 5,532,372 (issued Jul. 2, 1996) and Japanese Patent ApplicationJP 8-333368 (published Dec. 17, 1996), the present compounds exhibitunexpected properties, such as with respect to increased metabolicstability, oral bioavailability, safety and/or selectivity with respectto relevant receptors. In general, the present compounds possessrelatively high affinity antagonism for dopamine D2, serotonin 5-HT2A,α2C adrenergic receptors, partial agonism at 5-HT1A receptors and weakaffinity at 5-HT2C, histamine H1 and M1 receptors. Based on thisreceptor profile, the present compounds are expected to have efficacy onpositive and negative symptoms of schizophrenia. The present compoundsare also expected to be relatively well tolerated. The present compoundsare also expected to have a lower propensity for weight gain andtreatment related metabolic disorders relative to currently-marketedatypical antipsychotics.

The compounds of the present invention have utility in treating avariety of neurological and psychiatric disorders, including one or moreof the following conditions or diseases: schizophrenia or psychosisincluding schizophrenia (paranoid, disorganized, catatonic orundifferentiated), schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition andsubstance-induced or drug-induced (phencyclidine, ketamine and otherdissociative anaesthetics, amphetamine and other psychostimulants andcocaine) psychosispsychotic disorder, psychosis associated withaffective disorders, brief reactive psychosis, schizoaffectivepsychosis, “schizophrenia-spectrum” disorders such as schizoid orschizotypal personality disorders, or illness associated with psychosis(such as major depression, manic depressive (bipolar) disorder,Alzheimer's disease and post-traumatic stress syndrome), including boththe positive and the negative symptoms of schizophrenia and otherpsychoses; cognitive disorders including dementia (associated withAlzheimer's disease, ischemia, multi-infarct dementia, trauma, vascularproblems or stroke, HIV disease, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia,other general medical conditions or substance abuse); delirium, amnesticdisorders or age related cognitive decline; anxiety disorders includingacute stress disorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder, panic attack, panic disorder,post-traumatic stress disorder, separation anxiety disorder, socialphobia, specific phobia, substance-induced anxiety disorder and anxietydue to a general medical condition; substance-related disorders andaddictive behaviors (including substance-induced delirium, persistingdementia, persisting amnestic disorder, psychotic disorder or anxietydisorder; tolerance, dependence or withdrawal from substances includingalcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics);obesity, bulimia nervosa and compulsive eating disorders; bipolardisorders, mood disorders including depressive disorders; depressionincluding unipolar depression, seasonal depression and post-partumdepression, premenstrual syndrome (PMS) and premenstrual dysphoricdisorder (PDD), mood disorders due to a general medical condition, andsubstance-induced mood disorders; learning disorders, pervasivedevelopmental disorder including autistic disorder, attention disordersincluding attention-deficit hyperactivity disorder (ADHD) and conductdisorder; NMDA receptor-related disorders such as autism, depression,benign forgeffulness, childhood learning disorders and closed headinjury; movement disorders, including akinesias and akinetic-rigidsyndromes (including Parkinson's disease, drug-induced parkinsonism,postencephalitic parkinsonism, progressive supranuclear palsy, multiplesystem atrophy, corticobasal degeneration, parkinsonism-ALS dementiacomplex and basal ganglia calcification), medication-inducedparkinsonism (such as neuroleptic-induced parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremor), Gilles de laTourette's syndrome, epilepsy, muscular spasms and disorders associatedwith muscular spasticity or weakness including tremors; dyskinesias[including tremor (such as rest tremor, postural tremor and intentiontremor), chorea (such as Sydenham's chorea, Huntington's disease, benignhereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-inducedchorea and hemiballism), myoclonus (including generalised myoclonus andfocal myoclonus), tics (including simple tics, complex tics andsymptomatic tics),and dystonia (including generalised dystonia such asiodiopathic dystonia, drug-induced dystonia, symptomatic dystonia andparoxymal dystonia, and focal dystonia such as blepharospasm,oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis,axial dystonia, dystonic writer's cramp and hemiplegic dystonia)];urinary incontinence; neuronal damage including ocular damage,retinopathy or macular degeneration of the eye, tinnitus, hearingimpairment and loss, and brain edema; emesis; and sleep disordersincluding insomnia and narcolepsy.

Of the disorders above, the treatment of schizophrenia, bipolardisorder, depression including unipolar depression, seasonal depressionand post-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), learning disorders, pervasive developmentaldisorder including autistic disorder, attention disorders includingAttention-Deficit/Hyperactivity Disorder, autism,tic disorders includingTourette's disorder, anxiety disorders including phobia and posttraumatic stress disorder, cognitive disorders associated with dementia,AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease,spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment andloss are of particular importance.

In a specific embodiment, the present invention provides a method fortreating cognitive disorders, comprising: administering to a patient inneed thereof an effective amount of a compound of the present invention.Particular cognitive disorders are dementia, delirium, amnesticdisorders and age-related cognitive decline. At present, the textrevision of the fourth edition of the Diagnostic and Statistical Manualof Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington D.C.) provides a diagnostic tool that includes cognitivedisorders including dementia, delirium, amnestic disorders andage-related cognitive decline. As used herein, the term “cognitivedisorders” includes treatment of those mental disorders as described inDSM-IV-TR. The skilled artisan will recognize that there are alternativenomenclatures, nosologies and classification systems for mentaldisorders, and that these systems evolve with medical and scientificprogress. Thus the term “cognitive disorders” is intended to includelike disorders that are described in other diagnostic sources.

In another specific embodiment, the present invention provides a methodfor treating anxiety disorders, comprising: administering to a patientin need thereof an effective amount of a compound of the presentinvention. Particular anxiety disorders are generalized anxietydisorder, obsessive-compulsive disorder and panic attack. At present,the text revision of the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV-TR) (2000, AmericanPsychiatric Association, Washington D.C.) provides a diagnostic toolthat includes anxiety disorders are generalized anxiety disorder,obsessive-compulsive disorder and panic attack. As used herein, the term“anxiety disorders” includes treatment of those mental disorders asdescribed in DSM-IV-TR. The skilled artisan will recognize that thereare alternative nomenclatures, nosologies and classification systems formental disorders, and that these systems evolve with medical andscientific progress. Thus the term “anxiety disorders” is intended toinclude like disorders that are described in other diagnostic sources.

In another specific embodiment, the present invention provides a methodfor treating schizophrenia or psychosis comprising: administering to apatient in need thereof an effective amount of a compound of the presentinvention. Particular schizophrenia or psychosis pathologies areparanoid, disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder. At present, the text revision ofthe fourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington D.C.) provides a diagnostic tool that includes paranoid,disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder. As used herein, the term“schizophrenia or psychosis” includes treatment of those mentaldisorders as described in DSM-IV-TR. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies and classificationsystems for mental disorders, and that these systems evolve with medicaland scientific progress. Thus the term “schizophrenia or psychosis” isintended to include like disorders that are described in otherdiagnostic sources.

In another specific embodiment, the present invention provides a methodfor treating substance-related disorders and addictive behaviors,comprising: administering to a patient in need thereof an effectiveamount of a compound of the present invention. Particularsubstance-related disorders and addictive behaviors are persistingdementia, persisting amnestic disorder, psychotic disorder or anxietydisorder induced by substance abuse; and tolerance of, dependence on orwithdrawal from substances of abuse. At present, the text revision ofthe fourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington D.C.) provides a diagnostic tool that includes persistingdementia, persisting amnestic disorder, psychotic disorder or anxietydisorder induced by substance abuse; and tolerance of, dependence on orwithdrawal from substances of abuse. As used herein, the term“substance-related disorders and addictive behaviors” includes treatmentof those mental disorders as described in DSM-IV-TR. The skilled artisanwill recognize that there are alternative nomenclatures, nosologies andclassification systems for mental disorders, and that these systemsevolve with medical and scientific progress. Thus the term“substance-related disorders and addictive behaviors” is intended toinclude like disorders that are described in other diagnostic sources.

In another specific embodiment, the present invention provides a methodfor treating pain, comprising: administering to a patient in needthereof an effective amount of a compound of the present invention.Particular pain embodiments are bone and joint pain (osteoarthritis),repetitive motion pain, dental pain, cancer pain, myofascial pain(muscular injury, fibromyalgia), perioperative pain (general surgery,gynecological), chronic pain and neuropathic pain.

In another specific embodiment, the present invention provides a methodfor treating obesity or eating disorders associated with excessive foodintake and complications associated therewith, comprising: administeringto a patient in need thereof an effective amount of a compound of thepresent invention. At present, obesity is included in the tenth editionof the International Classification of Diseases and Related HealthProblems (ICD-10) (1992 World Health Organization) as a general medicalcondition. The text revision of the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV-TR) (2000, AmericanPsychiatric Association, Washington D.C.) provides a diagnostic toolthat includes obesity in the presence of psychological factors affectingmedical condition. As used herein, the term “obesity or eating disordersassociated with excessive food intake” includes treatment of thosemedical conditions and disorders described in ICD-10 and DSM-IV-TR. Theskilled artisan will recognize that there are alternative nomenclatures,nosologies and classification systems for general medical conditions,and that these systems evolve with medical and scientific progress. Thusthe term “obesity or eating disorders associated with excessive foodintake” is intended to include like conditions and disorders that aredescribed in other diagnostic sources.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reducation of risk of the diseases,disorders and conditions noted herein. The subject compounds are furtheruseful in a method for the prevention, treatment, control, amelioration,or reduction of risk of the aforementioned diseases, disorders andconditions in combination with other agents. The compounds of thepresent invention may be used in combination with one or more otherdrugs in the treatment, prevention, control, amelioration, or reductionof risk of diseases or conditions for which compounds of the presentinvention or the other drugs may have utility, where the combination ofthe drugs together are safer or more effective than either drug alone.Such other drug(s) may be administered, by a route and in an amountcommonly used therefor, contemporaneously or sequentially with acompound of the present invention. When a compound of the presentinvention is used contemporaneously with one or more other drugs, apharmaceutical composition in unit dosage form containing such otherdrugs and the compound of the present invention may be desireable.However, the combination therapy may also includes therapies in whichthe compound of the present invention and one or more other drugs areadministered on different overlapping schedules. It is also contemplatedthat when used in combination with one or more other active ingredients,the compounds of the present invention and the other active ingredientsmay be used in lower doses than when each is used singly. Accordingly,the pharmaceutical compositions of the present invention include thosethat contain one or more other active ingredients, in addition to acompound of the present invention. The above combinations includecombinations of a compound of the present invention not only with oneother active compound, but also with two or more other active compounds.Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. Accordingly, the pharmaceutical compositions of the presentinvention include those that also contain one or more other activeingredients, in addition to a compound of the present invention. Theweight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, such as about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Accordingly, the subject compounds may be used alone or in combinationwith other agents which are known to be beneficial in the subjectindications or other drugs that affect receptors or enzymes that eitherincrease the efficacy, safety, convenience, or reduce unwanted sideeffects or toxicity of the compounds of the present invention. Thesubject compound and the other agent may be co-administered, either inconcomitant therapy or in a fixed combination.

In one embodiment, the subject compound may be employed in combinationwith anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretaseinhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen,vitamin E, and anti-amyloid antibodies.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine,aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capuride, carbocloral, chloralbetaine, chloral hydrate, clomipramine, clonazepam, cloperidone,clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine,cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone,divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol,etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine,flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam,maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam,nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine,pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital,prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine,reclazepam, risperidone, roletamide, secobarbital, sertraline,suproclone, temazepam, thioridazine, thiothixene, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and saltsthereof, and combinations thereof, and the like, or the subject compoundmay be administered in conjunction with the use of physical methods suchas with light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.Lisuride and pramipexol are commonly used in a non-salt form.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone. It will be appreciated that theneuroleptic agents when used in combination with the subject compoundmay be in the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylate, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form. Thus, the subject compound may beemployed in combination with acetophenazine, alentemol, aripiprazole,amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine,chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine,haloperidol, levodopa, levodopa with benserazide, levodopa withcarbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide,olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine,risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine,thiothixene, trifluoperazine or ziprasidone.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid,phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine;duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone andviloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate,diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone,flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptablesalts thereof.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. This term in relation to pharmaceutical compositionsis intended to encompass a product comprising one or more activeingredients, and an optional carrier comprising inert ingredients, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. In general, pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients that are suitable for themanufacture of tablets. The tablets may be uncoated or they may becoated by known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredients are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions, oily suspensions,dispersible powders or granules, oil-in-water emulsions, and sterileinjectable aqueous or oleagenous suspension may be prepared by standardmethods known in the art.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reducation of risk of the diseases,disorders and conditions noted herein. The dosage of active ingredientin the compositions of this invention may be varied, however, it isnecessary that the amount of the active ingredient be such that asuitable dosage form is obtained. The active ingredient may beadministered to patients (animals and human) in need of such treatmentin dosages that will provide optimal pharmaceutical efficacy. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.0001 to 10mg/kg. of body weight daily are administered to the patient, e.g.,humans and elderly humans. The dosage range will generally be about 0.5mg to 1.0 g. per patient per day which may be administered in single ormultiple doses. In one embodiment, the dosage range will be about 0.5 mgto 500 mg per patient per day; in another embodiment about 0.5 mg to 200mg per patient per day; and in yet another embodiment about 5 mg to 50mg per patient per day. Pharmaceutical compositions of the presentinvention may be provided in a solid dosage formulation such ascomprising about 0.5 mg to 500 mg active ingredient, or comprising about1 mg to 250 mg active ingredient. The pharmaceutical composition may beprovided in a solid dosage formulation comprising about 1 mg, 5 mg, 10mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, such as 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, suchas once or twice per day.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsand the requisite intermediates are in some cases commerciallyavailable, or can be prepared according to literature procedures or asillustrated herein. The compounds of this invention may be prepared byemploying reactions as shown in the following schemes, in addition toother standard manipulations that are known in the literature orexemplified in the experimental procedures. Substituent numbering asshown in the schemes does not necessarily correlate to that used in theclaims and often, for clarity, a single substituent is shown attached tothe compound where multiple substituents are allowed under thedefinitions hereinabove. Reactions used to generate the compounds ofthis invention are prepared by employing reactions as shown in theschemes and examples herein, in addition to other standard manipulationssuch as ester hydrolysis, cleavage of protecting groups, etc., as may beknown in the literature or exemplified in the experimental procedures.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

EXAMPLE 1

Step 1:rac-(3aS,4S,7S,7aR)-tetrahydro-1H-4,7-methanoisoindole-1,3,5(4H)-trione

Chromium trioxide (2.7 g) was dissolved in concentrated sulfuric acid(2.3 mL) and water (10 mL). 12.17 mL of this solution was added dropwiseto a 0° C. solution of rac-(3aS, 4R, 5S, 7R,7aR)-5-hydroxyhexahydro-1H-4,7-methanoisoindole-1,3-dione (4.21 g)(prepared by modification of the procedures in Japanese PatentPublication JP 8-333368, Dec. 17, 1996) in 20 mL of acetone. After 1 hr,2-propanol (20 mL) was added, and the reaction was stirred 30 min(orange color dissipates). The reaction was filtered through celite andconcentrated in vacuo. Silica gel chromatography eluting with 98:2CH₂Cl₂:MeOH afforded 4 g of the titled compound as a white solid.

Step 2:rac-(3aS,4S,5R,7S,7aR)-5-hydroxy-5-methylhexahydro-1H-4,7-methanoisoindole-1,3-dione

To a −78° C. solution ofrac-(3aS,4S,7S,7aR)-tetrahydro-1H-4,7-methanoisoindole-1,3,5(4H)-trione(1.08 g, 6.03 mmol) (Kossakowski, Jerzy; Zawadowski, Teodor; Balicka,Eliza., Acta Poloniae Pharmaceutica (1997), 54(6), 479-481) in 50 ml ofanhydrous THF was added methylmagnesium bromide (5.02 ml of a 3 Msolution in THF, 15.07 mmol). After 2 hr, an additional 3 mL ofmethylmagnesium bromide solution was added. After another 2 hr, anadditional 2 mL of methylmagnesium bromide solution was added. After 6hr total at −78° C., the cooling bath was removed and the reactionallowed to warm to room temperature. The reaction was quenched withacetic acid (1.725 ml, 30.1 mmol) (Carefully). 200 uL of water wasadded, and the mixture was diluted with CH₂Cl₂ and 2 mL MeOH. Themixture was dried over Na₂SO₄, filtered, and concentrated to give awhite foam. The foam was dissolved in 5% MeOH/CH₂Cl₂ and filteredthrough a plug of silica to give the titled compound as an off-whitesolid.

Step 3:(3aS,4S,5R,7S,7aR)-2-[((1R,2R)-2-{[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]methyl}cyclohexyl)methyl]-5-hydroxy-5-methylhexahydro-1H-4,7-methanoisoindole-1,3-dione

and(3aR,4S,5S,7S,7aS)-2-[((1R,2R)-2-{[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]methyl}cyclohexyl)methyl]-5-hydroxy-5-methylhexahydro-1H-4,7-methanoisoindole-1,3-dione

To a solution ofrac-(3aS,4S,5R,7S,7aR)-5-hydroxy-5-methylhexahydro-1H-4,7-methanoisoindole-1,3-dione(88 mg, 0.451 mmol) in toluene (5 ml) and DMF (1.8 ml) were addedtrans-R,R-3a,7a-octahydroisoindolium-2-spiro-1′-[4′-(1,2-benzoisothiazol-3-yl)]piperazinemethanesulfonate (191 mg, 0.451 mmol) and potassium carbonate (125 mg,0.902 mmol). The reaction was heated at 110° C. for 23 h, then removedfrom heat. The mixture was partitioned between ethyl acetate and water,and the aqueous solution was washed once more with ethyl acetate. Thecombined organic solutions were dried (Na₂SO₄) and concentrated. Theresidue was purified by silica gel chromatography eluting withEtOAc/hexanes to give 189 mg of a mixture of the two titled compounds.Preparative HPLC (Chiralcel OD, 60% EtOH/hexanes+0.1% diethylamine)provided:(3aS,4S,5R,7S,7aR)-2-[((1R,2R)-2-{[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]methyl}cyclohexyl)methyl]-5-hydroxy-5-methylhexahydro-1H-4,7-methanoisoindole-1,3-dioneand(3aR,4S,5S,7S,7aS)-2-{[((1R,2R)-2-{[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]methyl}cyclohexyl)methyl]-5-hydroxy-5-methylhexahydro-1H-4,7-methanoisoindole-1,3-dione.(3aS,4S,5R,7S,7aR)-2-[((1R,2R)-2-{[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]methyl}cyclohexyl)methyl]-5-hydroxy-5-methylhexahydro-1H-4,7-methanoisoindole-1,3-dione.Retention time 4.6 min. ¹H NMR (CDCl₃) δ 7.91 (d, 1H, J=8 Hz); 7.80 (d,1H, J=8 Hz); 7.46 (t, 1H, J=8 Hz); 7.35 (t, 1H, J=8 Hz); 3.94 (dd, 1H,J=13, 4 Hz); 3.53 (t, 3H, J=5 Hz); 3.50 (d, 1H, J=7 Hz); 3.34 (dd, 1H,J=13, 10 Hz); 2.73 (d, 1H, J=7 Hz); 2.68-2.59 (m, 6 H); 2.48 (s, 1H);2.23 (dd, 1H, J=13, 7 Hz); 1.89 (br d, 1H, J=14 Hz); 1.74 (dd, 1H, J=13,5 Hz); 1.67 (br d, 2H, J=12 Hz); 1.61-1.51 (m, 3H); 1.48 (d, 2H, J=11Hz); 1.41 (s, 3H); 1.38 (dd, 1H, J=13, 3 Hz); 1.27-1.09 (m, 4H);1.06-0.96 (m, 2H). HRMS (ESI) calcd for C₂₉H₃₈N₄O₃S: 523.2738 [M+H]⁺;found: 523.2713. In Vitro Affinity (Ki) on Human Receptors: 5HT1A(native) 8 nM; α2C 9 nM; α2A 59 nM; D2 1 nM; 5HT2A<10 nM; D3 2 nM; 5HT2C16 nM; H1 371 nM; D1 457 nM; α1A 31 nM; α1D 82 nM; hERG 644 nM.Functional Potency (IC50) on Human Receptors: 5HT1A EC50=98 (77% max);α2C 160 nM; α2A 1217 nM; 5HT2A 32 nM; D2 25 nM; D1 1650 nM; 5HT2C 1707nM; H1 3100 nM; hERG 4000 nM.(3aR,4S,5S,7S,7aS)-2-[((1R,2R)-2-{[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]methyl}cyclohexyl)methyl]-5-hydroxy-5-methylhexahydro-1H-4,7-methanoisoindole-1,3-dione.Retention time 5.2 min. ¹H NMR (CDCl₃) δ 7.91 (d, 1H, J=8 Hz); 7.80 (d,1H, J=8 Hz); 7.46 (t, 1H, J=8 Hz); 7.35 (t, 1H, J=8 Hz); 3.95 (dd, 1H,J=13, 4 Hz); 3.53 (t, 3H, J=5 Hz); 3.50 (d, 1H, J=7 Hz); 3.34 (dd, 1H,J=13, 10 Hz); 2.73 (d, 1H, J=7 Hz); 2.68-2.59 (m, 6 H); 2.48 (s, 1H);2.23 (dd, 1H, J=13, 7 Hz); 1.89 (br d, 1H, J=13 Hz); 1.74 (dd, 1H, J=13,5 Hz); 1.70-1.46 (m, 7H); 1.41 (s, 3H); 1.37 (dd, 1H, J=13, 3 Hz);1.27-1.09 (m, 4H); 1.06-0.96 (m, 2H). HRMS (ESI) calcd for C₂₉H₃₈N₄O₃S:523.2738 [M+H]⁺; found: 523.2709.

Compounds in Table 1 were synthesized as shown above, but substitutingthe appropriately substitutedrac-(3aS,4S,5R,7S,7aR)-5-hydroxy-5-alkylhexahydro-1H-4,7-methanoisoindole-1,3-dioneas described in the Schemes and the foregoing examples. The requisitestarting materials were commercially available, described in theliterature or readily synthesized by one skilled in the art of organicsynthesis.

TABLE 1 Compound Nomenclature MS M + 1

(3aR,4S,5S,7S,7aS)-2- [((1R,2R)-2-{[4-(1,2- benzisothiazol-3-yl)piperazin-1- yl]methyl}cyclohexyl) methyl]-5-hydroxy-5-ethylhexahydro-1H-4,7- methanoisoindole-1,3- dione 537.2867

(3aS,4S,5R,7S,7aR)-2- [((1R,2R)-2-{[4-(1,2- benzisothiazol-3-yl)piperazin-1- yl]methyl}cyclohexyl) methyl]-5-hydroxy-5-ethylhexahydro-1H-4,7- methanoisoindole-1,3- dione 537.2863

(3aR,4S,5S,7S,7aS)-2- [((1R,2R)-2-{[4-(1,2- benzisothiazol-3-yl)piperazin-1- yl]methyl}cyclohexyl) methyl]-5-hydroxy-5-trifluoromethylhexahydro- 1H-4,7-methanoisoindole- 1,3-dione 577.2432

(3aS,4S,5R,7S,7aR)-2- [((1R,2R)-2-{[4-(1,2- benzisothiazol-3-yl)piperazin-1- yl]methyl}cyclohexyl) methyl]-5-hydroxy-5-trifluoromethylhexahydro- 1H-4,7-methanoisoindole- 1,3-dione 577.2433

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

1-20. (canceled)
 21. A compound which is:

or a pharmaceutically acceptable salt thereof.
 22. A pharmaceuticalcomposition which comprises a pharmaceutically acceptable carrier andthe compound of claim 21 or a pharmaceutically acceptable salt thereof.23. A method for treating schizophrenia in a mammalian patient in needthereof which comprises administering to the patient a therapeuticallyeffective amount of the compound of claim 21 or a pharmaceuticallyacceptable salt thereof.
 24. A method for treating bipolar disorder in amammalian patient in need thereof which comprises administering to thepatient a therapeutically effective amount of the compound of claim 21or a pharmaceutically acceptable salt thereof.
 25. A method for treatinganxiety in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of thecompound of claim 21 or a pharmaceutically acceptable salt thereof.